EBV infects approximately 95% of the human population resulting in a benign, lifetime latent infection of B lymphocytes. EBV is unique in that latent infection can lead to virus-associated malignancies such as Burkitt lymphoma (BL), Hodgkin lymphoma (HL), and non-Hodgkin lymphoma (NHL). These EBV-associated malignancies occur with high incidence in HIV/AIDS patients resulting in serious complications. Research in our laboratory has concentrated on understanding EBV latent infection and the resulting pathologies so that targeted therapies can be developed. Latent membrane protein 2A (LMP2A) is an EBV protein expressed in latently infected B-lymphocytes and detected in all EBV-associated malignancies including those seen in HIV/AIDS patients. LMP2A mimics normal B cell signaling pathways induced by the B cell receptor (BCR) and prevents apoptosis and prolongs cell survival. We have shown that LMP2A function is dependent on numerous cellular proteins including the cellular signal transducers Lyn, Syk, Abl, Akt, mTOR, Btk, BLNK, PI3-Kinase, and Ras. In our most recent studies, we have shown that LMP2A reduces the levels of p27, an important tumor suppressor that regulates the cell cycle. We also found that LMP2A simultaneously amplifies Myc expression. Thus, LMP2A provides two key hallmarks associated with the conversion of a normal cell to a cancer cell - prevention of apoptosis and activation of the cell cycle. In the current proposal, we plan to investigate the mechanism of p27 degradation and to identify the LMP2A activated proteins that target p27 for degradation using pharmacological inhibitors of LMP2A activated proteins. Ultimately, our studies may result in the development of novel treatments for EBV-related lymphoproliferative diseases that occur in HIV/AIDS patients, how these inhibitors work, and a better understanding of EBV latent infection in humans.